Abstract
Wnt signaling is known to regulate multiple processes including angiogenesis, inflammation, and fibrosis. Here, we identified a novel inhibitor of the Wnt pathway, pigment epithelium-derived factor (PEDF), a multifunctional serine proteinase inhibitor. Both overexpression of PEDF in transgenic mice and administration of PEDF protein attenuated Wnt signaling induced by retinal ischemia. Furthermore, PEDF knockdown by small interfering RNA (siRNA) and PEDF knockout in PEDF(-/-) mice induced activation of Wnt signaling. PEDF bound to LRP6, a Wnt coreceptor, with high affinity (K(d) [dissociation constant] of 3.7 nM) and blocked the Wnt signaling induced by Wnt ligand. The physical interaction of PEDF with LRP6 was confirmed by a coprecipitation assay, which showed that PEDF bound to LRP6 at the E1E2 domain. In addition, binding of PEDF to LRP6 blocked Wnt ligand-induced LRP6-Frizzled receptor dimerization, an essential step in Wnt signaling. These results suggest that PEDF is an endogenous antagonist of LRP6, and blocking Wnt signaling may represent a novel mechanism for its protective effects against diabetic retinopathy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Diabetic Retinopathy / physiopathology
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Eye Proteins / genetics
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Eye Proteins / metabolism*
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Humans
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LDL-Receptor Related Proteins / genetics
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LDL-Receptor Related Proteins / metabolism
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Low Density Lipoprotein Receptor-Related Protein-6
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Mice
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Mice, Knockout
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Mice, Transgenic
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Nerve Growth Factors / genetics
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Nerve Growth Factors / metabolism*
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Oxygen / toxicity
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptors, LDL / genetics
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Receptors, LDL / metabolism
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Retina / cytology
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Retina / metabolism
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Retina / pathology
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Serine Proteinase Inhibitors / genetics
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Serine Proteinase Inhibitors / metabolism*
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Serpins / genetics
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Serpins / metabolism*
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Signal Transduction / physiology*
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Wnt Proteins / antagonists & inhibitors*
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Wnt Proteins / genetics
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Wnt Proteins / metabolism*
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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Eye Proteins
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LDL-Receptor Related Proteins
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LRP6 protein, human
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Low Density Lipoprotein Receptor-Related Protein-6
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Lrp6 protein, mouse
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Nerve Growth Factors
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RNA, Small Interfering
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Receptors, LDL
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Serine Proteinase Inhibitors
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Serpins
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VLDL receptor
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Wnt Proteins
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beta Catenin
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pigment epithelium-derived factor
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Oxygen